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Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats.

Krishnan P, Yan KJ, Windler D, Tubbs J, Grand R, Li BD, Aldaz CM, McLarty J, Kleiner-Hancock HE - BMC Cancer (2009)

Bottom Line: Auraptene (10 microM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells.In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group.These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSUHSC-Shreveport, Louisiana, USA. hklein@lsuhsc.edu

ABSTRACT

Background: Breast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer.

Methods: The effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU) induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot.

Results: Auraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to the MNU only group (p < 0.05, n = 24-26). Auraptene (10 microM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells. In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group. Analysis of rat mammary tissue extract by HPLC with fluorescence detection indicated an average concentration (means +/- S.E.) of 1.4 +/- 0.5 microM and 1.8 +/- 0.3 microM in the normal mammary glands of the auraptene 200 ppm and 500 ppm groups, respectively. The concentration (means +/- S.E.) of auraptene in the mammary tumors of the auraptene 200 ppm group was 0.31 +/- 0.98 microM.

Conclusion: Overall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

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Effects of dietary auraptene on cyclin D1 expression in rat mammary tumors. From the same tumor study, rat mammary tumors were homogenized and the lysates were used for western blot to analyze the cyclin D1 expression. The top panel shows the representative blot. The bottom panel shows the graphical representation of the expression of cyclin D1. (+ statistically different from MNU group, * statistically different from Auraptene 200 group, p < 0.05, One-way ANOVA, Tukey test).
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Figure 5: Effects of dietary auraptene on cyclin D1 expression in rat mammary tumors. From the same tumor study, rat mammary tumors were homogenized and the lysates were used for western blot to analyze the cyclin D1 expression. The top panel shows the representative blot. The bottom panel shows the graphical representation of the expression of cyclin D1. (+ statistically different from MNU group, * statistically different from Auraptene 200 group, p < 0.05, One-way ANOVA, Tukey test).

Mentions: Based on the effect of auraptene on the expression of cyclin D1 expression in MCF-7 cells, the tumors from the rats were analyzed for cyclin D1 expression. Western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group (Figure 5). The effect of 500 ppm dose was also significantly different than the 200 ppm dose of auraptene, indicating a dose-response. We also observed that MNU increased eIF4E protein expression in the tumors compared to control mammary gland. Although cyclin D1 is known to be translationally regulated by eIF4E and other pathways [27], there was no significant change in the eIF4E protein expression by auraptene (data not shown).


Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats.

Krishnan P, Yan KJ, Windler D, Tubbs J, Grand R, Li BD, Aldaz CM, McLarty J, Kleiner-Hancock HE - BMC Cancer (2009)

Effects of dietary auraptene on cyclin D1 expression in rat mammary tumors. From the same tumor study, rat mammary tumors were homogenized and the lysates were used for western blot to analyze the cyclin D1 expression. The top panel shows the representative blot. The bottom panel shows the graphical representation of the expression of cyclin D1. (+ statistically different from MNU group, * statistically different from Auraptene 200 group, p < 0.05, One-way ANOVA, Tukey test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724550&req=5

Figure 5: Effects of dietary auraptene on cyclin D1 expression in rat mammary tumors. From the same tumor study, rat mammary tumors were homogenized and the lysates were used for western blot to analyze the cyclin D1 expression. The top panel shows the representative blot. The bottom panel shows the graphical representation of the expression of cyclin D1. (+ statistically different from MNU group, * statistically different from Auraptene 200 group, p < 0.05, One-way ANOVA, Tukey test).
Mentions: Based on the effect of auraptene on the expression of cyclin D1 expression in MCF-7 cells, the tumors from the rats were analyzed for cyclin D1 expression. Western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group (Figure 5). The effect of 500 ppm dose was also significantly different than the 200 ppm dose of auraptene, indicating a dose-response. We also observed that MNU increased eIF4E protein expression in the tumors compared to control mammary gland. Although cyclin D1 is known to be translationally regulated by eIF4E and other pathways [27], there was no significant change in the eIF4E protein expression by auraptene (data not shown).

Bottom Line: Auraptene (10 microM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells.In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group.These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSUHSC-Shreveport, Louisiana, USA. hklein@lsuhsc.edu

ABSTRACT

Background: Breast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer.

Methods: The effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU) induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot.

Results: Auraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to the MNU only group (p < 0.05, n = 24-26). Auraptene (10 microM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells. In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group. Analysis of rat mammary tissue extract by HPLC with fluorescence detection indicated an average concentration (means +/- S.E.) of 1.4 +/- 0.5 microM and 1.8 +/- 0.3 microM in the normal mammary glands of the auraptene 200 ppm and 500 ppm groups, respectively. The concentration (means +/- S.E.) of auraptene in the mammary tumors of the auraptene 200 ppm group was 0.31 +/- 0.98 microM.

Conclusion: Overall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

Show MeSH
Related in: MedlinePlus